Melanoma is a complex and deadly disease for which new therapies are needed. A major barrier to research and therapeutic breakthroughs, however, is the lack of mouse models properly resembling the human disease, and in particular, the human immune environment. The immune system profoundly affects physiological responses to tumor growth and metastasis in ways that are complex and incompletely understood. It is also known that the human immune system differs significantly from that of a mouse. Thus, there is a great need for better mouse models that enable in vivo studies of the interplay between human cancer and the human immune system, which would enable both mechanistic studies as well as the testing of combination therapies. To surmount this issue our group established MISTRG, a humanized mouse strain transplanted with human hematopoietic progenitor cells (HPCs) and expressing human versions of four genes encoding cytokines important for innate immune-cell development, most importantly human macrophages (MF). We showed that human MF infiltrated a human melanoma cell line-derived tumor in humanized MISTRG mice in a manner resembling that observed in tumors obtained from patients. This was associated with accelerated tumor progression and involved the pro-angiogenesis factor VEGF. These promising preliminary findings suggest that MISTRG is a valuable model for investigating the immune-mediated mechanisms of tumorigenesis. Here, we propose to extend these proof-of-concept experiments, and to credential the humanized MISTRG model, by establishing transcriptional signatures linked with melanoma progression and confirming these signatures in tumors from patients. Aim 1 will determine the architecture of human melanoma tumors and their impact on human tumor-infiltrating immune cells in vivo in MISTRG mice reconstituted with donor CD34+ HPCs and melanoma cell lines. Aim 2 will define how human melanoma alters the human systemic immunity in MISTRG mice. Aim 3 will validate the MISTRG model in an autologous system where MISTRG mice are reconstituted with patient CD34+ HPCs and autologous tumors. We expect this strategy to yield candidate therapeutic targets as well as a faithful and robust in vivo system for mechanistic studies aimed at unraveling key drivers of the relationship between the human immune system and human melanoma.